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UNDETECTED MALARIA - Recent evidence recognises the silent and persistent reservoir of parasites as one of the key drivers of continued malaria transmission. Asymptomatic malaria refers to a condition where individuals are infected with the malaria parasite but do not show noticeable symptoms. This is particularly a problem because asymptomatic infections are sources of parasites for mosquitoes to transmit to others, creating a ‘reservoir’ of infection within the human host. It is still unknown how some people show this asymptomatic infection state without presenting as an illness. This causes problems when trying to detect and treat these cases to stop further malaria transmission. A collaborative study between Imperial College London, London School of Hygiene & Tropical Medicine, and the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, explored the possibility that the response of blood cells of children with symptomatic or asymptomatic P. falciparum infections, assessed by genes turned on and off, would reveal how the asymptomatic infection state is maintained. If specific features of the asymptomatic malaria could be detected, they could lead to strategies to identify and eliminate the transmission reservoir, and built into malaria prevention programmes. Surprisingly, the results revealed the opposite of what was expected. Whilst symptomatic malaria induces large-scale changes in gene being turned on or off, the analysis of asymptomatically infected individuals showed no difference from uninfected healthy control children. In asymptomatic infections and the uninfected children, no genes were being switched on or off by the infection - in stark contrast to hundreds of genes being turned on and off for symptomatic malaria. The findings show that parasite numbers are staying below a limit needed to switch on any sort of immune response in the blood, leading to a malaria infection going “under the radar”. This means a human host stays healthy, does not seek treatment and the parasites can survive and be transmitted onwards. Co-author, Professor Aubrey Cunnington from the Department of Infectious Disease, explained “In many countries with a lot of malaria, asymptomatic infections can greatly outnumber the symptomatic ones. This causes problems because asymptomatic infections are a source of parasites for mosquitoes to transmit to others. The findings show that it will be difficult to develop simple blood tests which detect asymptomatically infected people based on their immune response.” Dr Julius Hafalla, Associate Professor of Immunology at London School of Hygiene and Tropical Medicine said: “If we want to detect asymptomatic individuals, we would need a more sensitive test for the parasites, which can detect lower levels of parasites than our conventional rapid diagnostic tests and microscopy. So, we are really talking about molecular tests like PCR.” Diana Ahu Prah, a PhD student who led the work at WACCBIP, University of Ghana, praised this important discovery as a step forward to create new diagnostics “the fact symptomatic malaria produces a strong response in the blood, as compared to asymptomatic cases, means that response could be the basis of future diagnostic tests to distinguish symptomatic malaria from other causes of fever. This would prevent the misclassification of patients who incidentally have parasites but actually have another cause of illness.” The authors also emphasise the importance of strengthening surveillance efforts, especially in countries nearing elimination, where this recent addition to our understanding of malaria provides a tool in the arsenal to create better diagnostics, vaccines, and treatment. Research published June 23 2023 in Journal of Infection: https://doi.org/10.1016/j.jinf.2023.06.013
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Scientists say mRNA technology could "open the floodgates" for developing vaccines against many other life-threatening conditions. BioNTech has announced plans to develop the world’s first mRNA-based malaria vaccine, in a potentially major step towards beating back the disease which still kills hundreds of thousands of people every year. The German pharmaceutical company produced its enormously successful Covid-19 vaccine along with the American giant Pfizer, and says it wants to start clinical trials of a shot to prevent malaria, made using similar technology, by 2022. Normal vaccines work by injecting a weakened or dead version of a germ into the human body to develop antibodies, but mRNA vaccines work differently. The new technology teaches cells how to make a protein that triggers an immune response, teaching the body to fight against future infections. "The very high efficacy of two mRNA vaccines for Covid-19 have shown the world just how powerful this technology could be against many diseases, including malaria," said Tedros Adhanom Ghebreyesus chief of World Health Organization, said last week. Earlier this year, the team behind the Oxford-AstraZeneca vaccine developed the first effective jab against the mosquito-borne disease, with a more than 75 per cent efficacy rate. The hope is that vaccines like this could help stop the enormous and needless loss of life every year in Africa. Roughly 400,000 people die every year of the disease in sub-Saharan Africa, more than half of whom are under the age of five. Progress in tackling the ancient disease has recently stalled. Moreover, after a year in which African nations have struggled to acquire anywhere near enough Covid-19 vaccines to immunise their populations - all of which are manufactured overseas - BioNTech said it is looking for suitable vaccine production sites on the continent. BioNTech said the company would fund the research and initial production of the vaccine itself. Then it will turn to partners for support with large-scale trials. Scientists have said that mRNA technology could "open the floodgates" for developing vaccines against many other life-threatening conditions. BioNTech also plans to start a clinical trial to test a vaccine against tuberculosis in 2022. The organisation is also receiving support from the European Commission and the Bill and Melinda Gates Foundation and the World Health Organisation.
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Juan Lama
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An international team of researchers has found that three commonly used antiviral and antimalarial drugs are effective in vitro at preventing replication of SARS-CoV-2, the virus that causes COVID-19. The work also underscores the necessity of testing compounds against multiple cell lines to rule out false negative results. The team, which included researchers from North Carolina State University and Collaborations Pharmaceuticals, looked at three antiviral drugs that have proven effective against Ebola and the Marburg virus: tilorone, quinacrine and pyronaridine. "We were looking for compounds that could block the entry of the virus into the cell," says Ana Puhl, senior scientist at Collaborations Pharmaceuticals and co-corresponding author of the research. "We chose these compounds because we know that other antivirals which successfully act against Ebola are also effective inhibitors of SARS-CoV-2." The compounds were tested in vitro against SARS-CoV-2, as well as against a common cold virus (HCoV 229E) and murine hepatitis virus (MHV). Researchers utilized a variety of cell lines that represented potential targets for SARS-CoV-2 infection in the human body. They infected the cell lines with the different viruses and then looked at how well the compounds prevented viral replication in the cells. The results were mixed, with the compounds' effectiveness depending upon whether they were used in human-derived cell lines versus monkey-derived cell lines, known as Vero cell lines. In the human-derived cell lines, we found that all three compounds worked similarly to remdesivir, which is currently being used to treat COVID-19," says Frank Scholle, associate professor of biology at NC State and co-author of the research. "However, they were not at all effective in the Vero cells." "Researchers saw similar results when these compounds were initially tested against Ebola," says Sean Ekins, CEO of Collaborations Pharmaceuticals and co-corresponding author of the research. "They were effective in human-derived cell lines, but not in Vero cells. This is important because Vero cells are one of the standard models used in this type of testing. In other words, different cells lines may have differing responses to a compound. It points to the necessity of testing compounds in many different cell lines to rule out false negatives." Next steps for the research include testing the compounds' effectiveness in a mouse model and further work on understanding how they inhibit viral replication. "One of the more interesting findings here is that these compounds don't just prevent the virus from potentially binding to the cells, but that they may also inhibit viral activity because these compounds are acting on the lysosomes," Puhl says. "Lysosomes, which are important for normal cell function, are hijacked by the virus for entry and exit out of the cell. So, if that mechanism is disrupted, it cannot infect other cells." "It's also interesting that these compounds are effective not just against SARS-CoV-2, but against related coronaviruses," Scholle says. "It could give us a head start on therapies as new coronaviruses emerge." Published in ACS Omega (March 10, 2021):
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Juan Lama
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A new genetic engineering technology could help eliminate malaria and stave off extinctions — if humanity decides to unleash it. One early summer evening in 2018, the biologist Anthony James drove from his office at the University of California, Irvine, to the headquarters of the Creative Artists Agency, a sleek glass-and-steel high-rise in Los Angeles. There, roughly 200 writers, directors and producers — many of them involved in the making of science-and-technology thrillers — were gathered for an event called Science Speed Dating, where James and other scientists would explain their work. The sessions were organized, James told me, “in hopes of getting the facts at least somewhat straight.” Attendees were assigned to different groups, so each scientist had just seven minutes to describe his or her work to one group before running to the next room and starting over. “There were a lot of stairs, so I would get really out of breath,” James recalled. “I would arrive panting.” He also felt a bit overwhelmed. There were executives in expensive suits, young men and women looking unaccountably dressy in ripped jeans and, according to James, a disconcerting number of people wearing hats. Few, if any, had a deep knowledge of genetics; one participant in particular kept referring to “the dark genome,” as though that were a thing. “I had to tell him, ‘Real geneticists don’t usually talk that way,’ ” James said. James began his presentation with a brief overview of mosquito-borne diseases like malaria and Zika. Then he turned cautiously to talking about his own area of scientific expertise: an obscure but powerful invention known as a gene drive. James began by noting that two brown-eyed human parents can sometimes produce a blue-eyed child, though only if both parents carry a copy of the recessive gene. A gene drive, he explained, was a tool that in some species could turn such events into a near certainty. For one thing, it guaranteed that a particular gene would be inherited, even if only one parent had it. And it would automatically insert the chosen gene into both copies of the offspring’s DNA, effectively turning a recessive trait into a dominant one. That alone, James explained, “lets you change the odds, so you get blue eyes 99 percent of the time.” What made the gene drive truly strange and remarkable, though, was that it didn’t stop with one set of offspring. Generation after generation, it would relentlessly copy and paste the gene it carried, until it was present in every descendant. “For most of the people in the room, you could tell it was the first they’d heard of this,” James recalled. “You could see their eyes getting big.” This mattered, James explained, because it allowed you to change not just a single creature but — potentially — an entire population, and quickly. A few months after the technique was discovered in 2014, James engineered two mosquitoes to carry a gene drive that was tied to a gene for red fluorescent color that would target the mosquitoes’ eyes. He then put each into a box with 30 ordinary purple-eyed mosquitoes. As the mosquitoes bred, they produced offspring: roughly 3,900 after two generations. (Mosquitoes lay a lot of eggs.) Under the normal rules of inheritance, there should have been an equal number of red-eyed and purple-eyed mosquitoes. Instead, when James opened the boxes to check on the offspring, all but 25 of the 3,900 mosquitoes had red eyes....
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Juan Lama
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Malaria kills about 500,000 people each year, about half of them children in Africa. The new vaccine isn’t perfect, but it will help turn the tide, experts said. The world has gained a new weapon in the war on malaria, among the oldest known and deadliest of infectious diseases: the first vaccine shown to help prevent the disease. By one estimate, it will save tens of thousands of children each year. Malaria kills about half a million people each year, nearly all of them in sub-Saharan Africa — including 260,000 children under 5. The new vaccine, made by GlaxoSmithKline, rouses a child’s immune system to thwart Plasmodium falciparum, the deadliest of five malaria pathogens and the most prevalent in Africa. The World Health Organization on Wednesday endorsed the vaccine, the first step in a process that should lead to wide distribution in poor countries. To have a malaria vaccine that is safe, moderately effective and ready for distribution is “a historic event,” said Dr. Pedro Alonso, director of the W.H.O.’s global malaria program. Malaria is rare in the developed world. There are just 2,000 cases in the United States each year, mostly among travelers returning from countries in which the disease is endemic. The vaccine, called Mosquirix, is not just a first for malaria — it is the first developed for any parasitic disease. Parasites are much more complex than viruses or bacteria, and the quest for a malaria vaccine has been underway for a hundred years. “It’s a huge jump from the science perspective to have a first-generation vaccine against a human parasite,” Dr. Alonso said. In clinical trials, the vaccine had an efficacy of about 50 percent against severe malaria in the first year, but the figure dropped close to zero by the fourth year. And the trials did not directly measure the vaccine’s impact on deaths, which has led some experts to question whether it is a worthwhileinvestment in countries with countless other intractable problems. But severe malaria accounts for up to half of malaria deaths and is considered “a reliable proximal indicator of mortality,” said Dr. Mary Hamel, who leads the W.H.O.’s malaria vaccine implementation program. “I do expect we will see that impact.” A modeling study last year estimated that if the vaccine were rolled out to countries with the highest incidence of malaria, it could prevent 5.4 million cases and 23,000 deaths in children younger than 5 each year. A recent trial of the vaccine in combination with preventive drugs given to children during high-transmission seasons found that the dual approach was much more effective at preventing severe disease, hospitalization and death than either method alone. The malaria parasite, carried by mosquitoes, is a particularly insidious enemy, because it can strike the same person over and over. In many parts of sub-Saharan Africa, even those where most people sleep under insecticide-treated bed nets, children have on average six malaria episodes a year. Even when the disease is not fatal, the repeated assault on their bodies can permanently alter the immune system, leaving them weak and vulnerable to other pathogens. Malaria research is littered with vaccine candidates that never made it past clinical trials. Bed nets, the most widespread preventive measure, cut malaria deaths in children under 5 only by about 20 percent. Against that backdrop, the new vaccine, even with modest efficacy, is the best new development in the fight against the disease in decades, some experts said. “Progress against malaria has really stalled over the last five or six years, particularly in some of the hardest hit countries in the world,” said Ashley Birkett, who heads malaria programs at PATH, a nonprofit organization focused on global health. With the new vaccine, “there’s potential for very, very significant impact there,” Dr. Birkett said. Mosquirix is given in three doses between ages 5 and 17 months, and a fourth dose roughly 18 months later. Following clinical trials, the vaccine was tried out in three countries — Kenya, Malawi and Ghana — where it was incorporated into routine immunization programs. More than 2.3 million doses have been administered in those countries, reaching more than 800,000 children. That bumped up the percentage of children protected against malaria in some way to more than 90 percent, from less than 70 percent, Dr. Hamel said. “The ability to reduce inequities in access to malaria prevention — that’s important,” Dr. Hamel said. “It was impressive to see that this could reach children who are currently not being protected.” It took years to create an efficient system to distribute insecticide-treated bed nets to families. By contrast, including Mosquirix among routine immunizations made it surprisingly easy to distribute, Dr. Hamel added — even in the midst of the coronavirus pandemic, which prompted lockdowns and disrupted supply chains. “We aren’t going to have to spend a decade trying to figure out how to get this to children,” she said. This week, a working group of independent experts in malaria, child health epidemiology and statistics, as well as the W.H.O.’s vaccine advisory group, met to review data from the pilot programs and to make their formal recommendation to Dr. Tedros Adhanom Ghebreyesus, director-general of the W.H.O. “We still have a very long road to travel, but this is a long stride down that road,” Dr. Tedros said at a news conference on Wednesday. The next step is for Gavi, the global vaccine alliance, to determine that the vaccine is a worthwhile investment. If the organization’s board approves the vaccine — not guaranteed, given the vaccine’s moderate efficacy and the many competing priorities — Gavi will purchase the vaccine for countries that request it, a process that is expected to take at least a year. But as with Covid-19, problems with vaccine production and supply could considerably delay progress. And the pandemic has also diverted resources and attention from other diseases, said Deepali Patel, who leads malaria vaccine programs at Gavi. “Covid is a big unknown in the room in terms of where capacity is currently in countries, and rolling out Covid-19 vaccines is a huge effort,” Ms. Patel said. “We’re really going to have to see how the pandemic unfolds next year in terms of when countries will be ready to pick up all of these other priorities.”
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A malaria vaccine has proved to be 77% effective in early trials and could be a major breakthrough against the disease, says the University of Oxford team behind it. Malaria kills more than 400,000 people a year, mostly children in sub-Saharan Africa. But despite many vaccines being trialled over the years, this is the first to meet the required target. The researchers say this vaccine could have a major public health impact. When trialled in 450 children in Burkina Faso, the vaccine was found to be safe, and showed "high-level efficacy" over 12 months of follow-up. Larger trials in nearly 5,000 children between the ages of five months and three years will now be carried out across four African countries to confirm the findings. Malaria is a life-threatening disease caused by parasites that are transmitted to people through mosquito bites. Although preventable and curable, the World Health Organization estimates there were 229 million cases worldwide in 2019 and 409,000 deaths. The illness starts with symptoms such as fever, headaches and chills and, without treatment, can progress quickly to severe illness and often death. Study author Adrian Hill, director of the Jenner Institute and professor of vaccinology at the University of Oxford, said he believed the vaccine was the first to reach the World Health Organization's goal of at least 75% efficacy. The most effective malaria vaccine to date had only shown 55% efficacy in trials on African children. The trials of this malaria vaccine started in 2019, long before coronavirus appeared - and the Oxford team developed its Covid vaccine (with AstraZeneca) on the strength of its research into malaria, Prof Hill said. A malaria vaccine has taken much longer to come to fruition because there are thousands of genes in malaria compared to around a dozen in coronavirus, and a very high immune response is needed to fight off the disease. "That's a real technical challenge," Prof Hill said. "The vast majority of vaccines haven't worked because it's very difficult." However, he said the trial results meant the vaccine was "very deployable" and "has the potential to have a major public health impact". 'Tool for saving lives' In a pre-print study with The Lancet, the research team - from Oxford, Nanoro in Burkina Faso and the US - reported the trial results of R21/Matrix-M, after testing a low and high dose of the vaccine in children, between May and August, before peak malaria season. The vaccine showed 77% efficacy in the higher-dose group and 71% in the lower-dose group. Halidou Tinto, professor in parasitology and the principal trial investigator at the Clinical Research Unit of Nanoro, Burkina Faso, said the results were "very exciting" and showed "unprecedented efficacy levels". "We look forward to the upcoming 'phase III' trial to demonstrate large-scale safety and efficacy data for a vaccine that is greatly needed in this region." In Africa, there have been more deaths from malaria than from coronavirus in the past year. The Serum Institute of India, which has manufactured the vaccine, says it is confident of delivering more than 200 million doses of the vaccine as soon as it is approved by regulators. Biotechnology company Novavax provided the adjuvant for the vaccine, an ingredient which is used to create a stronger immune response. Malaria is one of the leading causes of childhood mortality in Africa and Prof Charlemagne Ouédraogo, minister of health in Burkina Faso, said the new data showed that a new malaria vaccine could be licensed "in the coming years". "That would be an extremely important new tool for controlling malaria and saving many lives," he said. Preprint available in The Lancet (April 20, 2021):
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Researchers uncovered what they called “an enormous burden of dengue fever among children with undifferentiated febrile illness in Kenya.” Specifically, out of more than 1,000 children ill with fever, more than 40% were infected with dengue virus. Many children with dengue and without malaria were treated with antimalarial drugs, antimicrobial drugs or both, according to a report in Emerging Infectious Diseases. Dengue, which is endemic in more than 100 countries, “is an important cause of illness among children in Kenya, and clinicians should consider dengue as a cause of unlocalized fever,” Melisa M. Shah, MD, MPH, an endowed postdoctoral fellow at Stanford Medicine, told Healio. “Often, fever is considered to be malaria and empiric treatment is given,” Shah said. “The lack of awareness about dengue as a cause of febrile illness is one factor causing the overdiagnosis and overtreatment of malaria.” Shah and colleagues tested blood samples from 1,022 Kenyan children with ongoing febrile illness from 2014 to 2017. Of the 862 viable samples, dengue viremia was detected in 361 (41.9%). Of those 361 samples, 333 were classified as primary infections (92.2%), 14 were secondary infections (3.9%) and the remaining 14 samples lacked dengue virus immunoglobulin G data. Of the 1,022 study participants, 419 (41%) received antimalarial drugs, Shah and colleagues reported. Antimalarial drugs were more likely to be administered to patients with dengue virus viremia — 48.8% vs. 36.8%. Among 141 study participants who had confirmed dengue without malaria, 29 (20.6%) received an antimalarial drug (20.6%), 75 received an antimicrobial drug (53.2%) and 12 received both (8.5%). “The unnecessary use of antimalarials and antibiotics exposes children to known medication side effects and may contribute to the development of drug resistance,” Shah said. Participants with dengue virus viremia with febrile illness reported headaches (49.6%), poor appetite (46.8%), cough (45.7%) and joint pain (36.8%). “An accurate, reliable and affordable point-of-care diagnostic for dengue is urgently needed for health practitioners in outpatient settings in endemic areas,” Shah said. “Such a diagnostic could quickly identify whether dengue may be the cause of febrile illness.”... Published in Emerging Inf. Diseases (Oct. 14, 2020): https://doi.org/10.3201/eid2611.200960
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The female mosquito needs your blood to grow her eggs. Please don’t feel singled out. She bites everyone. There is no truth to the myths that mosquitoes prefer women over men or blondes and redheads over those with darker hair. She does, however, play favorites. Type O blood seems to be the vintage of choice. Stinky feet emit a bacterium that woos famished females, as do perfumes. As a parting gift, she leaves behind an itchy bump (an allergic reaction to her saliva) and potentially something far worse: infection with one of several deadly diseases, including malaria, Zika, West Nile, dengue and yellow fever. Mosquitoes are our apex predator, the deadliest hunter of human beings on the planet. A swarming army of 100 trillion or more mosquitoes patrol nearly every inch of the globe, killing about 700,000 people annually. Researchers suggest that mosquitoes may have killed nearly half of the 108 billion humans who have ever lived across our relatively brief 300,000 years of existence. Malarious mosquitoes patrolling the Pontine Marshes facilitated both the rise and the fall of the Roman Empire. Initially shielding the Eternal City from the Visigoths, Huns and Vandals, they eventually pointed their proboscises inward on Rome itself. Mosquitoes also played a role in steering slave ships from Africa across the Atlantic, because plantation owners in the Americas believed that Africans withstood the onslaught of mosquito-borne disease better than indigenous slaves or European indentured servants. Malaria, a parasitic disease, is the unsurpassed scourge of humankind. Dr. W. D. Tigertt, an early malariologist at Walter Reed Army Medical Center, said, “Malaria, like the weather, seems to have always been with the human race.” He continued, “And as Mark Twain said about the weather, it seems that very little is done about it.” Even today, more than 200 million unlucky people contract malaria each year. Mosquitoes also transmit a catalog of viruses: dengue, West Nile, Zika and various encephalitides. While debilitating, these diseases are generally not prolific killers. Yellow fever, however, is the viral exception. It can produce fever-induced delirium, liver damage bleeding from the mouth, nose and eyes, and coma. Internal corrosion induces vomit of blood, the color of coffee grounds, giving rise to the Spanish name for yellow fever, vómito negro (black vomit), which is sometimes followed by death. Today, roughly four billion people are at risk from mosquito-borne diseases. As our ancestors can attest, our battle with the mosquito has always been a matter of life and death, and it’s beginning to look as though this confrontation is coming to a head.
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